Ikaros sets thresholds for T cell activation and regulates chromosome propagation

T cell activation involves the sustained accumulation of T cell receptor (T CR) and IL-2 receptor (IL-2R) mediated signaling events that promote cell c ycle entry and progression. The Ikaros family of nuclear factors regulate t his process by providing thresholds overcome by receptor signaling. T cells with reduced levels of Ikaros activity require fewer TCR engagement events for activation, exhibit a greater proliferative response to IL-2, and are less sensitive to inhibitors of TCR and IL-2R signaling. Upon T cell activa tion, Ikaros proteins localize in a higher-order chromatin structure where they colocalize with components of the DNA replication machinery. Prolifera ting T cells with reduced Ikaros activity display chromosome abnormalities. We propose that participation of Ikaros in higher-order chromatin structur es controls cell cycle transitions and restricts DNA replication.